The insulin-like growth factor-I receptor (IGF-IR) is commonly overexpressed in malignancies. Furthermore, reduction in the expression using antisense strategies results in inhibition of tumor growth. To further understand the etiology of the overexpression of the IGF-IR in malignancies, we have characterized its proximal promoter region and started to investigate a number of transcription factors which control the expression of the IGF-IR gene. The tumor suppressor gene products WT1 and p53 inhibit IGF-IR promoter activity by apparently different mechanisms. WT1 binds to GC boxes in the 5' flanking and 5' UTR of the DNA via its zinc finger domain and inhibits the promoter activity. The p53, on the other hand, interferes with the formation of the transcription initiation complex. Mutations of the WT1 protein in the zinc finger region as well as those mutations in p53 commonly found in colonic and other cancers, increase the IGF-IR promoter activity and may explain the increased expression of the IGF-IR in Wilms~ tumor and other more common cancers. Interestingly, the EWS/WT1 fusion protein, caused by a chromosomal translocation that juxtaposes the N-terminal domain of the Ewings sarcoma protein (EWS) to the zinc finger domain of WT1, results in enhanced IGF-IR promoter activity. EWS/WT1 binds the WT1-related boxes on the DNA and enhances the promoter activity via the EWS transactivating domain. Finally, growth factors including bFGF and PDGF enhance IGF-IR gene expression by increasing promoter activity. Together these studies explain a number of mechanisms which are potentially responsible for the increased expression of the IGF-IR in many varied cancers.